Relapsed/Refractory Chronic Lymphocytic Leukemia and Relapsed/Refractory Small Lymphocytic Lymphoma
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of brexucabtagene autoleucel (KTE-X19) in adults with relapsed/refractory chronic lymphocytic leukemia (r/r CLL) and small lymphocytic lymphoma (r/r SLL) who have received at least 2 prior lines of treatment, one of which must include a Bruton's tyrosine kinase (BTK) inhibitor. After the end of KTE-C19-108, participants who received an infusion of brexucabtagene autoleucel will complete the remainder of the 15-year follow-up assessments in a separate Long-term Follow-up study, KT-US-982-5968 (NCT05041309).
Interventions
BIOLOGICALbrexucabtagene autoleucel
CAR-transduced autologous T cells administered intravenously
DRUGFludarabine
Administered intravenously
DRUGCyclophosphamide
Administered intravenously
Sponsors
Kite, A Gilead Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Documentation of relapsed or refractory CLL and SLL; must have received at least 2 prior lines of treatment, one of which must include a Bruton's tyrosine kinase (BTK) inhibitor. * Cohort 1 and 2: Participants with r/r CLL who have received at least 2 prior lines of treatment, one of which must include a BTK inhibitor. * Cohort 3: Participants with r/r CLL and SLL must present with ≤ 1% circulating tumor cells in peripheral blood or absolute lymphocyte count (ALC) \< 5000 cells/μL. Participants must have received at least 2 prior lines of treatment, one of which must include a BTK inhibitor. * Cohort 4: Participants with r/r CLL who have received at least 2 prior lines of treatment and must have received ibrutinib as a single agent or in comibation with anti-cluster of differentiate 20 (CD20) antibodies, B-cell lymphoma 2 (BCL-2) inhibitors, and phosphoinositide 3-kinase inhibitor (PI3k) inhibitors for at least 6 months as the last line of therapy prior to screening. Ibrutinib administration will continue up to 30 hours prior to leukapheresis. In case of treatment interruption with ibrutinib, the principal investigator should reach out to the medical monitor to discuss. * An indication for treatment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria and radiographically measurable disease (at least 1 lesion \> 1.5 cm in diameter) * Adequate hematologic function as indicated by: * Platelet count ≥ 50 × 10\^9/L * Neutrophil count ≥ 0.5 × 10\^9/L * Hemoglobin ≥ 8 g/dL unless lower values are attributable to CLL * Adequate renal, hepatic, cardiac and pulmonary function defined as: * Creatinine clearance (as estimated by Cockcroft-Gault) ≥ 60 mL/min * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL unless participant has Gilbert's syndrome * Left ventricular ejection fraction (LVEF) ≥ 50%, no evidence of pericardial effusion, no New York Heart Association (NYHA) class III or IV functional classification, no clinically significant arrhythmias * No clinically significant pleural effusion * Baseline oxygen saturation \> 92% on room air * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy or BTKi (ibrutinib or acalabrutinib) at the time the participant is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the participant is planned for leukapheresis (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists) Key
Exclusion criteria
* A history of treatment including any of the following: * Prior cluster of differentiate 19 (CD19) directed therapy * Prior allogeneic hematopoietic stem cell transplant (SCT) or donor lymphocyte infusion (DLI) within 6 months prior to enrollment * History of autoimmune disease resulting in end-organ injury unless attributable to CLL (eg, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA)) * Diagnosis of Richter's transformation or a history of malignancy other than non-melanoma skin cancer or carcinoma in situ (eg, skin, cervix, bladder, breast), superficial bladder cancer, asymptomatic localized low grade prostate cancer for which watch-and-wait approach is standard of care, or any other cancer that has been in remission for \> 3 years prior to enrollment * History of severe hypersensitivity reaction attributed to aminoglycosides Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | First infusion date of brexucabtagene autoleucel up to 28 days. Participants were evaluated in specified period but Grade 4 hematologic toxicity (specified in description) having onset in this period were further observed for 30 days for confirmation. | DLTs refer to toxicities with onset experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLTs evaluated may include with some exceptions: All brexucabtagene autoleucel related Grade 3 non-hematologic toxicities lasting for more than 7 days, Grade 4 non-hematologic toxicities regardless of duration, and Grade 4 hematologic toxicity lasting more than 30 days if not attributable to underlying disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | First infusion date up to last follow up visit (maximum duration: 42 months) | ORR was defined as percentage of participants achieving either complete response (CR), complete response with incomplete hematopoetic recovery (CRi) or partial response (PR). Criteria for CR: no lymphadenopathy \>1.5 cm or hepatomegaly/splenomegaly, lymphocytes \<4000/microliters (μL), bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules, platelets ≥100,000/µL, hemoglobin ≥11 grams per deciliter (g/dL). CRi: All CR criteria were met except with platelet count \<100,000/μL, hemoglobin \<11 g/dL or neutrophil count \<500/μL. PR: ≥1 of these: ≥50% decrease in lymphocytes, lymphadenopathy, size of liver and spleen, 50% decrease in bone marrow infiltrates; and ≥1 of these: platelets ≥100,000/µL or ≥50% increase from Baseline, hemoglobin ≥11 g/dL or ≥50% increase from Baseline. Participants who did not meet criteria were considered nonresponders. 95% confidence interval (CI) was calculated by Clopper-Pearson method. |
| Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | First infusion date up to last follow up visit (maximum duration: 42 months) | An AE is defined as any untoward medical occurrence in a clinical trial participant that does not necessarily have a relationship with study treatment or worsening of a pre-existing medical condition. TEAEs were defined as AEs with onset on or after the initiation of brexucabtagene autoleucel infusion. |
| Peak Level of Anti-CD19 CAR T-Cells in Blood | First infusion date up to 3 months post-infusion (approximately 3 months) | Peak was defined as the maximum number of CAR T cells measured post-infusion. |
Countries
Italy, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States and Italy. The study was terminated before enrolling participants in the Cohort 4B.
Pre-assignment details
17 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg Participants with r/r CLL received conditioning chemotherapy (fludarabine 30 mg/m\^2/day over 30 minutes and cyclophosphamide 500 mg/m\^2/day over 30-60 minutes) administered IV on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10\^6 anti-CD19 CAR T cells/kg administered IV on Day 0. | 6 |
| First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg Participants with r/r CLL received conditioning chemotherapy (fludarabine 30 mg/m\^2/day over 30 minutes and cyclophosphamide 500 mg/m\^2/day over 30-60 minutes) administered IV on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 2 x 10\^6 anti-CD19 CAR T cells/kg administered IV on Day 0. | 3 |
| Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg Participants with r/r CLL and SLL with ≤1% malignant cells in peripheral blood or ALC \< 5,000 cells/μL received conditioning chemotherapy (fludarabine 30 mg/m\^2/day over 30 minutes and cyclophosphamide 500 mg/m\^2/day over 30-60 minutes) administered IV on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10\^6 anti-CD19 CAR T cells/kg administered IV on Day 0. | 3 |
| Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg Participants with r/r CLL who previously received two lines of therapy along with ibrutinib with or without anti CD20 antibodies, BCL-2 and PI3k inhibitors received ibrutinib up to 30 hours prior to leukapheresis along with conditioning chemotherapy (fludarabine 30 mg/m\^2/day over 30 minutes and cyclophosphamide 500 mg/m\^2/day over 30-60 minutes) administered IV on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10\^6 anti-CD19 CAR T cells/kg administered IV on Day 0. | 3 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 2 | 3 | 0 | 1 |
| Overall Study | Enrolled but Never Treated | 1 | 0 | 0 | 0 |
| Overall Study | Reason not Specified | 3 | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg | First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg | Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 9 Participants |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 5.8 | 58.7 years STANDARD_DEVIATION 5.9 | 68.0 years STANDARD_DEVIATION 11.5 | 63.3 years STANDARD_DEVIATION 9.1 | 62.3 years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 3 Participants | 2 Participants | 13 Participants |
| Region of Enrollment Italy | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 6 Participants | 2 Participants | 3 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 7 | 3 / 3 | 0 / 3 | 1 / 3 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 4 / 6 | 2 / 3 | 3 / 3 | 1 / 3 |
Outcome results
Primary
Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
DLTs refer to toxicities with onset experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLTs evaluated may include with some exceptions: All brexucabtagene autoleucel related Grade 3 non-hematologic toxicities lasting for more than 7 days, Grade 4 non-hematologic toxicities regardless of duration, and Grade 4 hematologic toxicity lasting more than 30 days if not attributable to underlying disease.
Time frame: First infusion date of brexucabtagene autoleucel up to 28 days. Participants were evaluated in specified period but Grade 4 hematologic toxicity (specified in description) having onset in this period were further observed for 30 days for confirmation.
Population: DLT Evaluable Set included all participants treated with the target brexucabtagene autoleucel dose and followed for at least 28 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 1 Participants |
| Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria
ORR was defined as percentage of participants achieving either complete response (CR), complete response with incomplete hematopoetic recovery (CRi) or partial response (PR). Criteria for CR: no lymphadenopathy \>1.5 cm or hepatomegaly/splenomegaly, lymphocytes \<4000/microliters (μL), bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules, platelets ≥100,000/µL, hemoglobin ≥11 grams per deciliter (g/dL). CRi: All CR criteria were met except with platelet count \<100,000/μL, hemoglobin \<11 g/dL or neutrophil count \<500/μL. PR: ≥1 of these: ≥50% decrease in lymphocytes, lymphadenopathy, size of liver and spleen, 50% decrease in bone marrow infiltrates; and ≥1 of these: platelets ≥100,000/µL or ≥50% increase from Baseline, hemoglobin ≥11 g/dL or ≥50% increase from Baseline. Participants who did not meet criteria were considered nonresponders. 95% confidence interval (CI) was calculated by Clopper-Pearson method.
Time frame: First infusion date up to last follow up visit (maximum duration: 42 months)
Population: All Treated Subjects Set included all participants who were treated with any dose of brexucabtagene autoleucel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | 50 percentage of participants |
| First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg | Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | 33 percentage of participants |
| Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | 100 percentage of participants |
| Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | 0 percentage of participants |
Secondary
Peak Level of Anti-CD19 CAR T-Cells in Blood
Peak was defined as the maximum number of CAR T cells measured post-infusion.
Time frame: First infusion date up to 3 months post-infusion (approximately 3 months)
Population: Participants in the safety analysis set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Peak Level of Anti-CD19 CAR T-Cells in Blood | 1.46 cells/μL |
| First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg | Peak Level of Anti-CD19 CAR T-Cells in Blood | 1.08 cells/μL |
| Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Peak Level of Anti-CD19 CAR T-Cells in Blood | 42.18 cells/μL |
| Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Peak Level of Anti-CD19 CAR T-Cells in Blood | 1.00 cells/μL |
Secondary
Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a clinical trial participant that does not necessarily have a relationship with study treatment or worsening of a pre-existing medical condition. TEAEs were defined as AEs with onset on or after the initiation of brexucabtagene autoleucel infusion.
Time frame: First infusion date up to last follow up visit (maximum duration: 42 months)
Population: Safety Analysis Set included all participants who were treated with any dose of brexucabtagene autoleucel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |